Huntington's disease (HD) is a genetic neurodegenerative disease caused by an expanded CAG repeat in the human Huntingtin gene (HTT) that yields an expanded polyglutamine (polyQ) repeat in exon-1 of the human mutant huntingtin (mHTT) protein. The presence of this polyQ repeat results in neuronal degeneration, and there is no cure nor treatment that modifies disease progression. Small molecules that bind selectively to the recently-cloned sigma 2 receptor (2R), which is identical to TMEM97, have been shown to have neuroprotective effects in Alzheimer's disease, traumatic brain injury and several other neurological disorders. To assess whether modulating pathways involving 2R/TMEM97 can provide protection in HD, we used an HD cell model to evaluate the effects of 2R/TMEM97 ligands on mHTT induced neuronal toxicity. We first synthesized a set of compounds designed to bind to 2R/TMEM97, and binding profiles (Ki) of these ligands were determined. Modulators with high selectivity for 2R/TMEM97 relative to 1Rwere then tested in our HD cell model. Primary cortical neurons were cultured in vitro for seven days and then co-transfected with either normal HTT construct (Htt N-586-22Q/GFP) or mHTT construct (Htt-N586-82Q/GFP). Transfected neurons were treated with 2R/TMEM97 or 1R modulators for 48 h. After treatment, neurons were fixed and stained with Hoechst, and condensed nuclei were quantified to assess cell death in transfected neurons. Significantly, 2R/TMEM97 modulators reduce the neuronal toxicity induced by mHTT, and their neuroprotective effects are not blocked by NE-100, a selective 1R antagonist. These results indicate for the first time that 2R/TMEM97 modulators can protect neurons from mHTT induced neuronal toxicity, suggesting that targeting 2R/TMEM97 may provide a novel therapeutic approach to treat HD patients.
Neuroprotective Effects of σ2R/TMEM97 Receptor Modulators in Neuronal Model of Huntington's Disease
25 May 2022, Version 1
This content is a preprint and has not undergone peer review at the time of posting.